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  • 1
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 225-249 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: The gas-lift technique comprises the injection of gas bubbles in vertical oil wells to increase production. It is based on a reduction of the tubing gravitational pressure gradient. Several fluid-flow phenomena influencing such vertical gas-liquid flows are discussed. These effects include the radial distribution of void fraction and of gas and liquid velocity, flow regime changes, and system stability problems. Associated consequences for gas-lift performance and related optimization approaches are also discussed.
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  • 2
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 193-224 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: What mechanisms of flow control do animals use to enhance hydrodynamic performance? Animals are capable of manipulating flow around the body and appendages both passively and actively. Passive mechanisms rely on structural and morphological components of the body (i.e., humpback whale tubercles, riblets). Active flow control mechanisms use appendage or body musculature to directly generate wake flow structures or stiffen fins against external hydrodynamic loads. Fish can actively control fin curvature, displacement, and area. The vortex wake shed by the tail differs between eel-like fishes and fishes with a discrete narrowing of the body in front of the tail, and three-dimensional effects may play a major role in determining wake structure in most fishes.
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  • 3
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 395-425 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Over the past four decades, the combination of in situ and remote sensing observations has demonstrated that long nonlinear internal solitary-like waves are ubiquitous features of coastal oceans. The following provides an overview of the properties of steady internal solitary waves and the transient processes of wave generation and evolution, primarily from the point of view of weakly nonlinear theory, of which the Korteweg-de Vries equation is the most frequently used example. However, the oceanographically important processes of wave instability and breaking, generally inaccessible with these models, are also discussed. Furthermore, observations often show strongly nonlinear waves whose properties can only be explained with fully nonlinear models.
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  • 4
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 339-369 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: We consider the hydrodynamics of creatures capable of sustaining themselves on the water surface by means other than flotation. Particular attention is given to classifying water walkers according to their principal means of weight support and lateral propulsion. The various propulsion mechanisms are rationalized through consideration of energetics, hydrodynamic forces applied, or momentum transferred by the driving stroke. We review previous research in this area and suggest directions for future work. Special attention is given to introductory discussions of problems not previously treated in the fluid mechanics literature, with hopes of attracting physicists, applied mathematicians, and engineers to this relatively unexplored area of fluid mechanics.
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  • 5
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 27-63 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Race car performance depends on elements such as the engine, tires, suspension, road, aerodynamics, and of course the driver. In recent years, however, vehicle aerodynamics gained increased attention, mainly due to the utilization of the negative lift (downforce) principle, yielding several important performance improvements. This review briefly explains the significance of the aerodynamic downforce and how it improves race car performance. After this short introduction various methods to generate downforce such as inverted wings, diffusers, and vortex generators are discussed. Due to the complex geometry of these vehicles, the aerodynamic interaction between the various body components is significant, resulting in vortex flows and lifting surface shapes unlike traditional airplane wings. Typical design tools such as wind tunnel testing, computational fluid dynamics, and track testing, and their relevance to race car development, are discussed as well. In spite of the tremendous progress of these design tools (due to better instrumentation, communication, and computational power), the fluid dynamic phenomenon is still highly nonlinear, and predicting the effect of a particular modification is not always trouble free. Several examples covering a wide range of vehicle shapes (e.g., from stock cars to open-wheel race cars) are presented to demonstrate this nonlinear nature of the flow field.
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  • 6
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 277-307 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: We review mathematical models of confined bubbles, emphasizing physical mechanisms as expressed in simple geometries. Molecular interactions between liquid, gas, and the confining solid are all important and are described through the disjoining pressure concept. Methods for finding static shapes are considered. The static solution is a springboard for discussing pressure-driven and surface-tension-driven flows, both of which involve viscous effects and macroscopic films entrained near apparent contact lines. We next discuss vapor bubbles produced by thermal effects. Vaporization localized near contact lines and condensation distributed in colder parts of the interface lead to steady vapor bubbles. Their size is determined through global constraints. Unsteady vapor bubbles are discussed and we end with thoughts on open problems.
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  • 7
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 251-276 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: We review recent advances in understanding, modeling, and controlling oscillations in the flow past a cavity. The fundamental mechanisms underlying cavity flow oscillations have been known for at least 40 years, but suppressing these oscillations in a reliable and robust way is still a challenge today. Interest in controlling the flow past a cavity is motivated by aerospace applications, but in addition, cavity flows provide an attractive canonical problem for exploring general flow control techniques. The focus is on recent advances in modeling these flows, and in controlling them, using both open-loop and closed-loop techniques. A relatively new perspective is that cavity oscillations may not always be self-sustained, but under some flow conditions may be lightly damped resonances, sustained by external disturbances such as boundary layer turbulence. Areas in which our understanding is incomplete, and which deserve further study, are discussed, in particular the effects of high-frequency open-loop forcing, fundamental limitations of feedback control for a given configuration of sensors and actuators, and the development of a feedback design methodology that respects the limited range of validity of the available dynamical models.
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  • 8
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    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 499-511 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The behavioral and neuropsychiatric symptoms of dementia and Alzheimer's disease have become an increasingly important focus of clinical research. These symptoms also pose a tremendous challenge to families and caregivers. The late afternoon/evening exacerbation of behavioral symptoms in dementia has been recognized by clinicians for 〉60 years. Researchers have utilized a variety of increasingly sophisticated tools to examine the circadian, hormonal, physiological, and epidemiological correlations with sundowning behavior. Although treatment remains largely empirical, an improved understanding of the complex relationships that drive sundowning behavior should lead to more effective therapies in the future.
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  • 9
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 575-590 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: In the short time since it became effective for health care organizations, a privacy regulation issued under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) has had a significant adverse impact on the conduct of clinical research in the United States, without a substantial corresponding increase in privacy protection for research participants. Some of the problems associated with HIPAA have been resolved through revisions since the regulation's initial promulgation in December 2000, and other problems can be addressed by better educating health care providers and researchers about its requirements and available alternatives for compliance; however, considerable structural challenges remain. These constitute substantial barriers to research and resulting medical advances. Additional revisions to HIPAA based on the principles and trade-offs reflected in the Common RuleĐ??which responsibly balances an individual's interest in privacy protection with the public interest in gaining knowledge through biomedical researchĐ??can go a long way to remedying remaining flaws in the system.
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  • 10
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 473-484 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: We review the clinical and genetic disorders associated with exercise-induced ventricular arrhythmias in patients with normal hearts. Foremost are those with catecholaminergic polymorphic ventricular tachycardia due to abnormalities in either the ryanodine receptor 2 genes (RyR2) or the calsequestrin genes (CASQ). These patients manifest ventricular premature beats and polymorphic ventricular tachycardia in response to exercise or on exposure to catecholamines. A great deal of basic information has been accumulated suggesting that these arrhythmias are caused by abnormalities in Ca2+ metabolism. The ensuing cytosolic Ca2+ overload results in delayed after-depolarizations and extrasystolic Ca2+ waves, leading to polymorphic ventricular tachycardia. Most of these patients will respond to beta-blocker therapy but a significant minority (30%) will require a defibrillator. Advances in genetic testing allow better understanding of this syndrome.
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  • 11
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 167-180 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Rotavirus is the single most common cause of acute, dehydrating gastroenteritis worldwide. This is a highly contagious and highly democratic disease. The attack rate in infants and young children is similar regardless of sanitation, socioeconomics or geography. Rotavirus vaccine development began in the early 1980s using a "Jennerian" approach based on rotaviruses that normally infect animals. Although these vaccines were found to be generally safe, protection from disease was inconsistent. The second generation of vaccines was based on the same animal viruses configured to carry the relevant coat proteins of human rotaviruses. An attenuated human rotavirus vaccine has also been developed. After close to 20 years of laboratory and clinical studies, safe and effective rotavirus vaccines are approaching regulatory approval.
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  • 12
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 455-471 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: More than three decades of clinical experience in cardiac transplantation resulted in the spread of the procedure worldwide with a wealth of knowledge and advancements. Developments included liberalization of recipient and donor selection criteria, improved surgical techniques, novel immunosuppressive drugs and protocols, new rejection surveillance techniques, and better understanding of the pathophysiology of cardiac allograft vasculopathy to direct interventions for prevention and treatment.
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  • 13
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 491-505 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The sodium-hydrogen exchanger regulatory factors (NHERF-1 and NHERF-2) are a family of adaptor proteins characterized by the presence of two tandem PDZ protein interaction domains and a C-terminal domain that binds the cytoskeleton proteins ezrin, radixin, moesin, and merlin. The NHERF proteins are highly expressed in the kidney, small intestine, and other organs, where they associate with a number of transporters and ion channels, signaling proteins, and transcription factors. Recent evidence has revealed important associations between the NHERF proteins and several G proteinĐ??coupled receptors such as the ?‚2-adrenergic receptor, the ?”-opioid receptor, and the parathyroid hormone receptor, as well as growth factor tyrosine kinase receptors such as the platelet-derived growth factor receptor and the epidermal growth factor receptor. This review summarizes the emerging data on the biochemical mechanisms, physiologic outcomes, and potential clinical implications of the assembly and disassembly of receptor/NHERF complexes.
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  • 14
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 345-374 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Phosphorylation of Ser19 on the 20-kDa regulatory light chain of myosin II (MLC20) by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca2+]i transient is rapidly dissipated and MLCK inactivated, whereas MLC20 and muscle contraction are well maintained. Sustained contraction does not reflect Ca2+ sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca2+ induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca2+-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca2+ concentrations, involves (a) G protein activation, (b) regulated inhibition of MLC phosphatase, and (c) MLC20 phosphorylation via a Ca2+-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by Gq/13-coupled receptors are initiated by sequential activation of Gʼ̛q/ʼ̛13, RhoGEF, and RhoA, and involve Rho kinaseĐ??mediated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-mediated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. Sustained MLC20 phosphorylation is probably induced by the Ca2+-independent MLCK, ZIP kinase. The pathways initiated by Gi-coupled receptors involve sequential activation of G?‚??i, PI 3-kinase, and the Ca2+-independent MLCK, integrin-linked kinase. The last phosphorylates MLC20 directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC2 and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities. These kinases also act downstream to inhibit (a) initial contraction by inhibiting Ca2+ mobilization and (b) sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC20 dephosphorylation and muscle relaxation.
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  • 15
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 685-717 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Ion channels are pore-forming transmembrane proteins that allow ions to permeate biological membranes. Pore structure plays a crucial role in determining the ion permeation and selectivity properties of particular channels. In the past few decades, efforts have been undertaken to identify key elements of the pore regions of different classes of ion channels. In this review, we summarize current knowledge about permeation and selectivity of channel proteins from the transient receptor potential (TRP) superfamily. Whereas all TRP channels are permeable for cations, only two TRP channels are impermeable for Ca2+ (TRPM4, TRPM5), and two others are highly Ca2+ permeable (TRPV5, TRPV6). Despite the great advances in the TRP channel field during the past decade, only a limited number of reports have dealt with functional characterization of pore properties, biophysical aspects of cation permeation, or description of pore structures of TRP channels. This review gives an overview of available experimental and theoretical data and discusses the functional impact of pore-structure modifications on TRP channel properties.
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  • 16
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 461-490 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The serum/glucocorticoid-induced kinase Sgk1 plays an important role in the regulation of epithelial ion transport. This kinase is very rapidly regulated at the transcriptional level as well as via posttranslational modifications involving phosphorylation by the MAP or PI-3 kinase pathways and/or ubiquitylation. Although Sgk1 is a cell survival kinase, its primary role likely concerns the regulation of epithelial ion transport, as suggested by the phenotype of Sgk1-null mice, which display a defect in Na+ homeostasis owing to disturbed renal tubular Na+ handling. In this review we first discuss the molecular, cellular, and regulatory aspects of Sgk1 and its paralogs. We then discuss its roles in the physiology and pathophysiology of epithelial ion transport.
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  • 17
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 27-53 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Traditional approaches to the study of cognition emphasize an information-processing view that has generally excluded emotion. In contrast, the recent emergence of cognitive neuroscience as an inspiration for understanding human cognition has highlighted its interaction with emotion. This review explores insights into the relations between emotion and cognition that have resulted from studies of the human amygdala. Five topics are explored: emotional learning, emotion and memory, emotion's influence on attention and perception, processing emotion in social stimuli, and changing emotional responses. Investigations into the neural systems underlying human behavior demonstrate that the mechanisms of emotion and cognition are intertwined from early perception to reasoning. These findings suggest that the classic division between the study of emotion and cognition may be unrealistic and that an understanding of human cognition requires the consideration of emotion.
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  • 18
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 139-166 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Although the functions of sleep remain largely unknown, one of the most exciting hypotheses is that sleep contributes importantly to processes of memory and brain plasticity. Over the past decade, a large body of work, spanning most of the neurosciences, has provided a substantive body of evidence supporting this role of sleep in what is becoming known as sleep-dependent memory processing. We review these findings, focusing specifically on the role of sleep in (a) memory encoding, (b) memory consolidation, (c) brain plasticity, and (d) memory reconsolidation; we finish with a summary of the field and its potential future directions.
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  • 19
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 255-284 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: In this chapter we review theoretical and empirical advances in research on adolescent development in interpersonal and societal contexts. First, we identify several trends in current research, including the current emphasis on ecological models and the focus on diversity in and relational models of adolescent development. Next, we discuss recent research on interpersonal relationships, with an eye toward identifying major research themes and findings. Research on adolescents' relationships with parents, siblings, other relatives, peers, and romantic partners, and adolescents' involvement in community and society is reviewed. Future directions in research on adolescent development are discussed.
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  • 20
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 375-400 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Legitimacy is a psychological property of an authority, institution, or social arrangement that leads those connected to it to believe that it is appropriate, proper, and just. Because of legitimacy, people feel that they ought to defer to decisions and rules, following them voluntarily out of obligation rather than out of fear of punishment or anticipation of reward. Being legitimate is important to the success of authorities, institutions, and institutional arrangements since it is difficult to exert influence over others based solely upon the possession and use of power. Being able to gain voluntary acquiescence from most people, most of the time, due to their sense of obligation increases effectiveness during periods of scarcity, crisis, and conflict. The concept of legitimacy has a long history within social thought and social psychology, and it has emerged as increasingly important within recent research on the dynamics of political, legal, and social systems.
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  • 21
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 585-611 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Affirmative action is a controversial and often poorly understood policy. It is also a policy that has been widely studied by social scientists. In this review, we outline how affirmative action operates in employment and education settings and consider the major points of controversy. In addition, we detail the contributions of psychologists and other social scientists in helping to demonstrate why affirmative action is needed; how it can have unintended negative consequences; and how affirmative action programs can be most successful. We also review how psychologists have examined variations in people's attitudes toward affirmative action, in part as a means for testing different theories of social behavior.
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  • 22
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 505-528 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: This article argues that ideal longitudinal research is characterized by the seamless integration of three elements: (a) a well-articulated theoretical model of change observed using (b) a temporal design that affords a clear and detailed view of the process, with the resulting data analyzed by means of (c) a statistical model that is an operationalization of the theoretical model. Two general varieties of theoretical models are considered: models in which the time-related change of primary interest is continuous, and those in which it is characterized by movement between discrete states. In addition, two general types of temporal designs are considered: the longitudinal panel design and the intensive longitudinal design. For each general category of theoretical models, some of the analytic possibilities available for longitudinal panel designs and for intensive longitudinal designs are discussed. The article concludes with brief discussions of two issues particularly relevant to longitudinal researchĐ??missing data and measurementĐ??and a few words about exploratory research.
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  • 23
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 189-213 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
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    Annual Review of Pharmacology 46 (2006), S. 277-300 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The main role of blood platelets is to ensure primary hemostasis, which is the maintenance of vessel integrity and cessation of bleeding upon injury. While playing a major part in acute arterial thrombosis, platelets are also involved in inflammation, atherosclerosis, and angiogenesis. ADP and ATP play a crucial role in platelet activation, and their receptors are potential targets for antithrombotic drugs. The ATP-gated cation channel P2X1 and the two G proteinĐ??coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus. Owing to its central role in the growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs such as clopidogrel. Studies in P2Y1 and P2X1 knockout mice and selective P2Y1 and P2X1 antagonists have shown that these receptors are also attractive targets for new antithrombotic compounds. The potential role of platelet P2 receptors in the involvement of platelets in inflammatory processes is also discussed.
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 481-519 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VIĐ??and to some degree TM-VIIĐ??around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.
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    Annual Review of Pharmacology 46 (2006), S. 215-234 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: New methods to measure thiol oxidation show that redox compartmentation functions as a mechanism for specificity in redox signaling and oxidative stress. Redox Western analysis and redox-sensitive green fluorescent proteins provide means to quantify thiol/disulfide redox changes in specific subcellular compartments. Analyses using these techniques show that the relative redox states from most reducing to most oxidizing are mitochondria 〉 nuclei 〉 cytoplasm 〉 endoplasmic reticulum 〉 extracellular space. Mitochondrial thiols are an important target of oxidant-induced apoptosis and necrosis and are especially vulnerable to oxidation because of the relatively alkaline pH. Maintenance of a relatively reduced nuclear redox state is critical for transcription factor binding in transcriptional activation in response to oxidative stress. The new methods are applicable to a broad range of experimental systems and their use will provide improved understanding of the pharmacologic and toxicologic actions of drugs and toxicants.
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: I am honored to write the prefatory chapter for the inaugural volume of the Annual Review of Pathology: Mechanisms of Disease. This publishing venture signals that pathology takes its rightful place alongside the other biomedical sciences. I thought it may be of interest to some to delineate how a circuitous path led me into a career in experimental pathology and to give some of the flavor of a past era in experimental approaches. Thus, my title.
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    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Kaposi's sarcoma (KS) has long been suspected of having an infectious etiology on the basis of its unusual epidemiology, histopathology, and natural history. Nearly a decade ago, a novel herpesviral genome was discovered in KS biopsies, and since that time strong epidemiologic evidence has accumulated correlating infection with this KS-associated herpesvirus (KSHV, also known as human herpesvirus 8) with the development of the disease. Here we review the evidence linking KSHV infection to KS risk and discuss current notions of how KSHV gene expression promotes the development of this remarkable neoplasm. These studies show that both latent and lytic viral replicative cycles contribute significantlyĐ??but differentlyĐ??to KS development. The studies also highlight mechanistic differences between oncogenesis caused by KSHV and that caused by its distant relative Epstein-Barr virus.
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    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The endothelial cells lining vascular and lymphatic vessels are targets of several infectious agents, including viruses and bacteria, that lead to dramatic changes in their functions. Understanding the pathophysiological mechanisms that cause the clinical manifestations of those infections has been advanced through the use of animal models and in vitro systems; however, there are also abundant studies that explore the consequences of endothelial infection in vitro without supporting evidence that endothelial cells are actual in vivo targets of infection in human diseases. This article defines criteria for considering an infection as truly endothelium-targeted and reviews the literature that offers insights into the pathogenesis of human endothelial-target infections.
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    ISSN: 1553-4006
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Neurodegenerative diseases as diverse as Alzheimer's, Parkinson's, and Creutzfeldt-Jakob disease share a common pathogenetic mechanism involving aggregation and deposition of misfolded proteins, which leads to progressive central nervous system disease. Although the type of aggregated protein and the regional and cellular distribution of deposition vary from disease to disease, these disorders may all be linked by similar pathways of protein aggregation with fibril formation and amyloid deposition. This perspective on pathogenesis suggests that a wide variety of neurodegenerative diseases can be grouped mechanistically as brain amyloidoses, an outlook that yields novel insights into potential therapeutic approaches that may be applicable across the broad spectrum of neurodegenerative disease.
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    Annual Review of Entomology 51 (2006), S. 495-523 
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Aquatic insects and other benthic invertebrates are the most widely used organisms in freshwater biomonitoring of human impact. Because of the high monetary investment in freshwater management, decisions are often based on biomonitoring results, and a critical and comparative review of different approaches is required. We used 12 criteria that should be fulfilled by an "ideal" biomonitoring tool, addressing the rationale, implementation, and performance of a method. After illustrating how the century-old but still widely used Saprobian system does not meet these criteria, we apply them to nine recent approaches that range from the suborganismal to the ecosystem level. Although significant progress has been made in the field, no recent approach meets all 12 criteria. Given that the use of biomonitoring information has important financial consequences, we suggest that societies and governments prioritize how these criteria should be ranked.
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    Annual Review of Entomology 51 (2006), S. 413-440 
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: The mating system of each species is a unique, dynamic suite of interactions between the sexes. In this review I describe these interactions in the families of flies that contain blood-feeding species. A transition from the aerial swarm, with rapid copulae and no direct female choice, to substrate-based systems with lengthy copulae and opportunities for female choice is evident at both a phylogenetic scale and within nematoceran families under specific ecological conditions. Female monogamy is associated with the former, polyandry with the latter. I suggest that the intensity of sexual selection operating on males in systems where the probability of mating is low has favored male ability to control female receptivity. Reproductive success of males is universally correlated to successful foraging for sugar or blood and (in some species and ecological conditions) to body size. Understanding the ecological basis of the mating systems of these flies will help formulate integrative, sustainable, and biologically lucid approaches for their control.
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    Annual Review of Entomology 51 (2006), S. 259-284 
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Throughout its long evolutionary history, the Dopa decarboxylase gene (Ddc) has acquired a variety of functions in insects. The enzyme (DDC) catalyzes the production of the neural transmitters dopamine and serotonin. Not surprisingly, evidence of the enzyme's involvement in the behavior of insects is beginning to accumulate. In addition, DDC plays a role in wound healing, parasite defense, pigmentation, and cuticle hardening. A high degree of sequence conservation has allowed comparisons of the Ddc-coding regions from various insects, facilitating a number of recent studies on insect systematics. This review outlines the diverse functions of Ddc and illustrates how studies of this model system address many questions on insect neurobiology, developmental biology, and systematics.
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    Annual Review of Entomology 51 (2006), S. 581-608 
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Although best known for cooperation, insect societies also manifest many potential conflicts among individuals. These conflicts involve both direct reproduction by individuals and manipulation of the reproduction of colony members. Here we review five major areas of reproductive conflict in insect societies: (a) sex allocation, (b) queen rearing, (c) male rearing, (d) queen-worker caste fate, and (e) breeding conflicts among totipotent adults. For each area we discuss the basis for conflict (potential conflict), whether conflict is expressed (actual conflict), whose interests prevail (conflict outcome), and the factors that reduce colony-level costs of conflict (conflict resolution), such as factors that cause workers to work rather than to lay eggs. Reproductive conflicts are widespread, sometimes having dramatic effects on the colony. However, three key factors (kinship, coercion, and constraint) typically combine to limit the effects of reproductive conflict and often lead to complete resolution.
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    Annual Review of Entomology 51 (2006), S. 285-308 
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Interest in trap cropping, a traditional tool of pest management, has increased considerably in recent years. In this review we propose a broader definition of trap cropping that encompasses the inherent characteristics of the trap crop plants themselves as well as the strategies associated with their deployment. Inherent characteristics of a trap crop may include not only natural differential attractiveness for oviposition and feeding, but also other attributes that enable the trap crop plants to serve as a sink for insects or the pathogens they vector. Successful deployment of trap crops within a landscape depends on the inherent characteristics of the trap crop and the higher value crop, the spatial and temporal characteristics of each, the behavior and movement patterns of insect pests, and the agronomic and economic requirements of the production system. Thus, trap cropping is more knowledge-intensive than many other forms of pest management. We review recent references on trap cropping, classify them according to their modalities and level of implementation, and provide a synthesis of the factors that influence the success of trap cropping. Last, we provide a list of recommendations and guidelines that should prove helpful in moving trap cropping forward to its full potential.
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    Annual Review of Entomology 51 (2006), S. 137-161 
    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Boreal peat bogs contain distinctive insects in addition to widely distributed generalists, including species restricted to bogs (tyrphobionts) and species characteristic of bogs but not confined to them (tyrphophiles). Bogs raised above the water table form characteristic habitat islands in southern boreal and temperate forest zones. Many bogs have persisted for hundreds and even thousands of years, preserving relict ecosystems related to subarctic biomes. The historical development and nature of individual bogs are reflected by differences among their insects, which are of great biogeographical and ecological interest. The environmental sensitivity of bogs also makes insects valuable as bioindicators. Moreover, few readily accessible bogs remain in a natural state. Given the scientific interest of bog insects and the fact that each relict bog habitat island is unique, further studies of the diversity of bog faunas are merited, and the conservation of these habitats should be strongly supported by entomologists.
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    Annual Review of Fluid Mechanics 38 (2006), S. 111-128 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Wind tunnels have wide-ranging functionality, including many applications beyond aeronautics, and historically have been the major source of information for technological aerodynamics/aeronautical applications. There are a myriad of scaling issues/differences from flight to wind tunnel, and their study and impacts are uneven and a function of the particular type of extant flow phenomena. Typically, the most serious discrepancies are associated with flow separation. The tremendous ongoing increases in numerical simulation capability are changing and in many aspects have changed the function of the wind tunnel from a (scaled) "predictor" to a source of computational calibration/validation information with the computation then utilized as the flight prediction/scaling tool. Numerical simulations can increasingly include the influences of the various scaling issues. This wind tunnel role change has been occurring for decades as computational capability improves in all aspects. Additional issues driving this trend are the increasing cost (and time) disparity between physical experiments and computations, and increasingly stringent accuracy requirements.
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    Annual Review of Fluid Mechanics 38 (2006), S. 427-452 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: When the free surfaces of most solids approach their bulk melting temperatures from below, the molecular structure of the material gives way to a disordered structure with some attributes of both the solid and liquid phases. When the temperature is sufficiently close to that of bulk transition, the surface melts and literally flows as a viscous fluid. This phenomenon, called interfacial premelting, lies at the heart of the microscopic theory of melting of solid matter, and captures the interest of condensed matter physicists and physical chemists alike. The process is ubiquitous and responsible for a wide range of consequences in materials with biological, geophysical, and technological significance. Because such systems are often exposed to spatial or temporal variations in thermodynamic forcing, there are a host of fluid mechanical phenomena that result from this underlying melting behavior. The fluid dynamics of unfrozen surfaces holds clues for understanding the bulk behavior of polycrystalline materials, from Earth's mantle to the stratosphere and beyond. In this review we focus on the fluid dynamical consequences of the premelting of solids.
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    Annual Review of Fluid Mechanics 38 (2006), S. 1-25 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Brooke Benjamin's original theories of fluid mechanical phenomena changed our basic understanding of cavitation bubbles, surface and internal waves, gravity currents, instabilities of shear flow over flexible surfaces, and swirling flows. For some types of finite-amplitude wave phenomena, he generated integral constraints and derived new partial differential equations; by establishing their general properties he showed how they have wide application. He developed a complementary approach based on functional analysis that was quite new to fluid mechanics. He demonstrated methods for deriving, without detailed calculation, the essential features of nonlinear and indeterminate flow problems that are otherwise intractable.
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    Annual Review of Fluid Mechanics 38 (2006), S. 129-157 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: The challenges in understanding hypersonic flight are discussed and critical hypersonic aerothermodynamics issues are reviewed. The ability of current analytical methods, numerical methods, ground testing capabilities, and flight testing approaches to predict hypersonic flow are evaluated. The areas where aerothermodynamic shortcomings restrict our ability to design and analyze hypersonic vehicles are discussed, and prospects for future capabilities are reviewed. Considerable work still needs to be done before our understanding of hypersonic flow will allow for the accurate prediction of vehicle flight characteristics throughout the flight envelope from launch to orbital insertion.
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    Annual Review of Medicine 57 (2006), S. 437-454 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Stent-assisted carotid angioplasty (CAS) is increasingly utilized for hemodynamically significant stenoses of the extracranial carotid artery. Carotid endarterectomy (CEA) is still considered the gold standard in the management of symptomatic hemodynamically significant carotid stenoses. However, endovascular device technology is rapidly evolving and the recent introduction of embolic filtration devices (EFD) proved to reduce periprocedural stroke rates in CAS considerably. Several randomized multicenter trials are currently recruiting patients to compare CAS with EFD to carotid endarterectomy in different cohorts, such as patients at high surgical risk for CEA and those with asymptomatic stenosis. The review presents current developments in CAS.
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    Annual Review of Medicine 57 (2006), S. 331-347 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: A number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.
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    Annual Review of Medicine 57 (2006), S. 1-18 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Angiogenesis inhibitors for the treatment of cancer have now been approved by the Food and Drug Administration in the United States, and in 28 other countries including China. Clinical application of this new class of drugs is informed by certain principles from angiogenesis research. Oncogenic mutations initiate tumorigenesis, but angiogenesis is necessary for expansion of tumor mass. Two angiogenesis inhibitors have been developed that have a broad spectrum of anticancer activity, yet virtually no side effects. Endogenous angiogenesis inhibitors act as tumor suppressor proteins. The angiogenic response in vivo is based on the genetic background of the host. Several types of angiogenesis inhibitors reveal a biphasic, U-shaped curve of efficacy. "Antiangiogenic chemotherapy" is a novel approach to the treatment of drug resistance.
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    Annual Review of Medicine 57 (2006), S. 207-221 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Celiac disease is an autoimmune disease that occurs in genetically predisposed individuals as the result of an immune response to gluten. This immune response occurs in both the lamina propria and the epithelium of the small intestine. There is a close link to HLA DQ2 and DQ8, although these HLA genes account for only 40% of the genetic influence. Environmental factors, such as the amount and timing of gluten administration in infancy, as well as breastfeeding, influence the disease. Serologic screening studies that use sensitive and specific antibody tests have revealed the disease to be common, occurring in Đ♯1% of the population. Clinical presentations are diverse and atypical; the majority of patients lack diarrhea. Therapy is a gluten-free diet that requires avoidance of wheat, rye, and barley, although there is potential for other therapies based on our understanding of the pathophysiology of the disease.
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    Annual Review of Medicine 57 (2006), S. 155-166 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Hepatitis B is a global health problem. Patients with chronic hepatitis B (CHB) carry a significant risk to eventually develop cirrhotic liver disease. Recent therapeutic advances against CHB offer excellent potential for long-term suppression of hepatitis B virus (HBV) replication during antiviral therapy, and occasionally a durable remission off medication. Selection of appropriate patients for antiviral therapy depends on identification of HBV replication and an elevated alanine aminotransferase level or histologic liver injury. Pegylated interferon alpha offers potent immunomodulatory and antiviral activity with the potential for durability, but also with adverse effects and significant cost. The nucleoside or nucleotide analogs, lamivudine, adefovir, and entecavir, suppress HBV replication and are extremely well-tolerated, but long-term or even lifelong therapy is required. Most experience has been gained with lamivudine, but viral resistance occurs frequently. Newer analogs appear to be relatively free of this problem. Approaches using a combination of agents have promise, but have yet to be proven superior to individual drugs alone.
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    Annual Review of Medicine 57 (2006), S. 83-97 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The use of molecular approaches has become part of the standard of care in the management of pediatric cancer patients. Molecular approaches are now included in the initial diagnosis, definition of prognostically distinct patient subgroups, selection of patients for specific therapies, prediction of risk for toxicities to therapy, and monitoring of patients receiving both conventional and novel targeted therapies. This clinical application of molecular medicine has been based on a growing molecular understanding of cancer biology. Studies of pediatric cancers have contributed to this understanding in many ways. We present a model for understanding cancer biology, using specific examples taken from pediatric oncology, and then discuss the application of molecular techniques to the clinical management of pediatric cancer patients.
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    Annual Review of Medicine 57 (2006), S. 181-194 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: West Nile virus (WNV) was first detected in North America in 1999 during an outbreak of encephalitis in New York City. Since then the virus has spread across North America and into Canada, Latin America, and the Caribbean. The largest epidemics of neuroinvasive WNV disease ever reported occurred in the United States in 2002 and 2003. This paper reviews new information on the epidemiology and clinical aspects of WNV disease derived from greatly expanded surveillance and research on WNV during the past six years.
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    Annual Review of Medicine 57 (2006), S. 265-281 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate ?‚-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in ?‚-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet ?‚-cell that lead to stimulation of ?‚-cell replication and inhibition of ?‚-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances ?‚-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands ?‚-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve ?‚-cell mass, although it remains unclear whether TZDs affect ?‚-cell mass via direct mechanisms. Complementary approaches to regeneration of ?‚-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in ?‚-cell mass that is characteristic of the natural history of type 2 diabetes.
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    Annual Review of Medicine 57 (2006), S. 119-137 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Pharmacogenetics deals with inherited differences in the response to drugs. The best-recognized examples are genetic polymorphisms of drug-metabolizing enzymes, which affect about 30% of all drugs. Loss of function of thiopurine S-methyltransferase (TPMT) results in severe and life-threatening hematopoietic toxicity if patients receive standard doses of mercaptopurine and azathioprine. Gene duplication of cytochrome P4502D6 (CYP2D6), which metabolizes many antidepressants, has been identified as a mechanism of poor response in the treatment of depression. There is also a growing list of genetic polymorphisms in drug targets that have been shown to influence drug response. A major limitation that has heretofore moderated the use of pharmacogenetic testing in the clinical setting is the lack of prospective clinical trials demonstrating that such testing can improve the benefit/risk ratio of drug therapy.
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    Annual Review of Medicine 57 (2006), S. 195-206 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: We review the diagnosis, categorization, and treatment of prostatitis/chronic pelvic pain syndrome based on the National Institutes of Health (NIH) classification. Prostatitis is an extremely common syndrome that afflicts 2%Đ??10% of men. Formerly a purely clinical diagnosis, prostatitis is now classified within a complex series of syndromes (NIH category IĐ??IV prostatitis) that vary widely in clinical presentation and response to treatment. Acute bacterial prostatitis (category I) and chronic bacterial prostatitis (category II) are characterized by uropathogenic infections of the prostate gland that respond well to antimicrobial treatment. In contrast, chronic prostatitis/chronic pelvic pain syndrome (category III), which accounts for 90%Đ??95% of prostatitis cases, is of unknown etiology and is marked by a mixture of pain, urinary, and ejaculatory symptoms with no uniformly effective therapy. Asymptomatic inflammatory prostatitis (category IV) is an incidental finding of unknown clinical significance. This review describes the current status of prostatitis syndromes and explores the future prospects of new diagnostic tools and therapies.
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    Annual Review of Medicine 57 (2006), S. 365-380 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Various disciplines within nephrology investigate the mechanisms by which kidneys fail. Progress in the areas of glomerular hemodynamics, proteinuria, tubular biology, interstitial nephritis, fibroblast formation, and fibrosis have added kernels of information that together support a unified theory of renal progression. Prevention of progression to end-stage disease has largely focused on control of systemic and glomerular hypertension. Current success in delaying a decline in glomerular filtration rate underlines the promise of a more comprehensive approach. New knowledge about the cell biology of progression also suggests that other adjunctive therapies may be possible. We describe the progress and highlight those spheres where new-targeted interventions may arise.
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    Annual Review of Medicine 57 (2006), S. 349-364 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: It has long been recognized that the secretion of PTH by chief cells in the parathyroid gland is regulated by extracellular ionized calcium. The molecular mechanism by which extracellular Ca2+ performs this feat was deduced by the cloning of the extracellular calcium-sensing receptor (CaSR) in 1993 in the laboratories of Brown and Hebert. The CaSR is a G proteinĐ??coupled cell surface receptor that belongs to family 3 of the GPCR superfamily. The CaSR senses the extracellular ionic activity of the divalent minerals Ca2+ and Mg2+ and translates this information, via a complex array of cellular signaling pathways, to modify cell and tissue function. Genetic studies have demonstrated that the activity of this receptor determines the steady-state plasma calcium concentration in humans by regulating key elements in the calcium homeostatic system. CaSR agonists (calcimimetics) and antagonists (calcilytics) have been identified and have provided both current and potential therapies for a variety of disorders. Calcimimetics can effectively reduce PTH secretion in all forms of hyperparathyroidism. They are likely to become a major therapy for secondary hyperparathyroidism associated with renal failure and for treatment of certain patients with primary hyperparathyroidism. On the therapeutic horizon are calcilytics that can transiently increase PTH and may prove useful in the treatment of osteoporosis.
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    Annual Review of Medicine 57 (2006), S. 553-574 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Although used for more than 4000 years for recreational and medicinal purposes, Cannabis and its best-known pharmacologically active constituents, the cannabinoids, became a protagonist in medical research only recently. This revival of interest is explained by the finding in the 1990s of the mechanism of action of the main psychotropic cannabinoid, ??9-tetrahydrocannabinol (THC), which acts through specific membrane receptors, the cannabinoid receptors. The molecular characterization of these receptors allowed the development of synthetic molecules with cannabinoid and noncannabinoid structure and with higher selectivity, metabolic stability, and efficacy than THC, as well as the development of antagonists that have already found pharmaceutical application. The finding of endogenous agonists at these receptors, the endocannabinoids, opened new therapeutic possibilities through the modulation of the activity of cannabinoid receptors by targeting the biochemical mechanisms controlling endocannabinoid tissue levels.
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    Annual Review of Medicine 57 (2006), S. 535-551 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Existing treatments for neuropathic pain deliver inadequate pain relief, unacceptable side effects, or both. The unmet medical need for more effective treatment is driving a large volume of research to discover new drugs. Most existing treatments are drugs introduced to treat other pain conditions or other medical conditions, such as antidepressants and anticonvulsants, which were found empirically to be effective for neuropathic pain. Only recently have drug discovery efforts have become mechanistically driven, addressing targets identified by a molecular neurobiological approach to the pathophysiology of neuropathic states.
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    Annual Review of Medicine 57 (2006), S. 513-533 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.
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    Annual Review of Medicine 57 (2006), S. 65-81 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: MAbs directed toward tumor cells, tumor neovasculature, and host negative immunoregulatory elements (checkpoints) have emerged as useful immunotherapeutic agents against cancer. However, effective active modulation of the immune response with anticancer vaccines will require identifying appropriate tumor-rejection antigens; optimizing the interactions of peptides, antigen-presenting cells, and T cells; and blockading negative immunological checkpoints that impede an effective immune response. Checkpoints being targeted include CTLA-4 and PD1 that are negative signaling receptors expressed on activated T cells, CD4+CD25+ Foxp3-expressing Tregs (suppressor T cells), IL-2-mediated activation-induced cell death (AICD), and the cytokine TGF?‚.
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    Annual Review of Medicine 57 (2006), S. 313-329 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Dyslipidemia is the sine qua non of atherosclerosis, but it is also strongly associated with the metabolic syndrome, obesity, diabetes, and fatty liver disease. The molecular basis for future therapies requires understanding the pivotal role of nuclear hormone receptors in lipid and inflammatory homeostasis. This review summarizes evidence that the liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are key transcriptional regulators in lipid metabolism. Additionally, their effects on glucose homeostasis and inflammation make LXR and PPAR signaling networks attractive molecular targets for managing lipid-related diseases.
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    Annual Review of Medicine 57 (2006), S. 485-498 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Modern cancer therapy employs a combination of chemotherapy, antibody-based therapy, radiotherapy, and surgery to prolong life and provide cure. However, many of the chemotherapy agents and antibodies, either singly or in combination, can affect the cardiovascular system. Common cardiovascular manifestations of these therapies include heart failure, ischemia, hypotension, hypertension, edema, QT prolongation, bradyarrhythmia, and thromboembolism. The patient's age, underlying cardiovascular status, and genetic background, as well as the route of drug administration and dosage, can all contribute to the development of cardiotoxicity. Strategies to monitor for and to manage these effects are discussed in this review.
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    Annual Review of Medicine 57 (2006), S. 243-264 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Obesity is a major epidemic in developed countries. It induces or exacerbates hypertension, diabetes mellitus, obstructive sleep apnea, dyslipidemia, and many other disease processes, which cumulatively contribute to premature mortality on a scale rivaling that of smoking. At present, bariatric surgery is the only therapeutic modality that can produce sustained weight loss and halt or resolve comorbidities. This success results from the ability to perform the operation reliably, usually laparoscopically, with low mortality. The most commonly performed operation is Roux-en-Y gastric bypass. Other bypasses discussed in this review include biliopancreatic diversion with and without duodenal switch. Purely restrictive operations, especially adjustable gastric banding, have a lower risk but are somewhat less effective. We focus on the more controversial aspects of commonly accepted operations, including patient selection, the spectrum and frequency of complications, and the long-term outcome.
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    Annual Review of Medicine 57 (2006), S. 223-241 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded, normally soluble, protein. About 23 different unrelated proteins are known to form amyloid fibrils in vivo, which share a pathognomonic structure although they are associated with clinically distinct conditions. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls, and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries. This rarity and the variable involvement of different organs and tissues are often responsible for missed or delayed diagnosis, and amyloidosis remains a considerable clinical challenge. However, recent elucidation of important aspects of pathogenesis, as well as developments in diagnosis, monitoring, and treatment, have greatly improved outcomes, especially when patients are managed in specialist centers.
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    Annual Review of Medicine 57 (2006), S. 139-154 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Influenza A viral infection causes substantial annual morbidity and mortality worldwide, particularly for infants, the elderly, and the immunocompromised. The virus mainly replicates in the respiratory tract and is spread by respiratory secretions. A growing concern is the recent identification of H5N1 strains of avian influenza A in Asia that were previously thought to infect only wild birds and poultry, but have now infected humans, cats, pigs, and other mammals, often with fatal results, in an ongoing outbreak. A human pandemic with H5N1 virus could potentially be catastrophic because most human populations have negligible antibody-mediated immunity to the H5 surface protein and this viral subtype is highly virulent. Whether an H5N1 influenza pandemic will occur is likely to hinge on whether the viral strains involved in the current outbreak acquire additional mutations that facilitate efficient human-to-human transfer of infection. Although there is no historical precedent for an H5N1 avian strain causing widespread human-to-human transmission, some type of influenza A pandemic is very likely in the near future. The possibility of an H5N1 influenza pandemic has highlighted the many current limitations of treatment with antiviral agents and of vaccine production and immunogenicity. Future vaccine strategies that may include more robust induction of T-cell responses, such as cytotoxic T lymphocytes, may provide better protection than is offered by current vaccines, which rely solely or mainly on antibody neutralization of infection.
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    Annual Review of Medicine 57 (2006), S. 19-31 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Advances in radiation oncology have been made on three major fronts: biology, physics, and clinical application. Our biological understanding of how radiation kills cells and how malignant cells avoid damage has identified new targets for therapeutic manipulation. Research in physics has yielded sophisticated methods to direct the deposition of radiation energy in ways that enhance target coverage while minimizing dose to normal structures as much as possible. Intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy represent new paradigms in treatment planning and dose delivery. Clinical management of the cancer patient is multidisciplinary. Increasingly, combinations of radiation and chemotherapy, with or without surgery, are enhancing cure rates, often with preservation of organ function. Taken together, these advances have increased the effectiveness of radiation therapy and promise better treatment results in the future.
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    Annual Review of Medicine 57 (2006), S. 49-63 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. The Prostate Cancer Prevention Trial has provided the first firm evidence that this cancer can be prevented by a relatively nontoxic oral agent. Additional agents, many of which are antioxidants with antiandrogenic effects, are being tested (or soon will be) in large clinical trials. The current body of evidence is insufficient to make a routine recommendation of any dietary or nutritional supplement for the prevention of prostate cancer.
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    Annual Review of Physiology 68 (2006), S. 97-121 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although there have been important advances in diagnostic modalities and therapeutic strategies for congenital heart defects (CHD), these malformations still lead to significant morbidity and mortality in the human population. Over the past 10 years, characterization of the genetic causes of CHD has begun to elucidate some of the molecular causes of these defects. Linkage analysis and candidate-gene approaches have been used to identify gene mutations that are associated with both familial and sporadic cases of CHD. Complementation of the human studies with developmental studies in mouse models provides information for the roles of these genes in normal development as well as indications for disease pathogenesis. Biochemical analysis of these gene mutations has provided further insight into the molecular effects of these genetic mutations. Here we review genetic, developmental, and biochemical studies of six cardiac transcription factors that have been identified as genetic causes for CHD in humans.
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    Annual Review of Psychology 57 (2006), S. 1-26 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: This chapter begins with a summary of a model, developed half a century ago, that distinguishes three qualitatively different processes of social influence: compliance, identification, and internalization. The model, originally geared to and experimentally tested in the context of persuasive communication, was subsequently applied to influence in the context of long-term relationships, including psychotherapy, international exchanges, and the socialization of national/ethnic identity. It has been extended to analysis of the relationship of individuals to social systems. Individuals' rule, role, and value orientations to a systemĐ??conceptually linked to compliance, identification, and internalizationĐ??predict different reactions to their own violations of societal standards, different patterns of personal involvement in the political system, and differences in attitude toward authorities and readiness to obey. In a further extension of the model, three approaches to peacemaking in international or intergroup conflicts are identifiedĐ??conflict settlement, conflict resolution, and reconciliationĐ??which, respectively, focus on the accommodation of interests, relationships, and identities, and are conducive to changes at the level of compliance, identification, and internalization.
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    Annual Review of Psychology 57 (2006), S. 117-137 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: The study of the genetics of complex behaviors has evolved dramatically from the days of the nature versus nurture debates that dominated much of the past century. Here we discuss advances in our understanding of the genetics of affective and anxiety disorders. In particular, we highlight our growing understanding of specific gene-environment interactions that occur during critical periods in development, setting the stage for later behavioral phenotypes. We review the recent literature in the field, focusing on recent advances in our understanding of the role of the serotonin system in establishing normal anxiety levels during development. We emphasize the importance of understanding the effect of genetic variation at the level of functional circuits and provide examples from the literature of how such an approach has been exploited to study novel genetic endpoints, including genetically based variation in response to medication, a potentially valuable phenotype that has not received much attention to date.
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    Annual Review of Psychology 57 (2006), S. 227-254 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: The study of explanation, while related to intuitive theories, concepts, and mental models, offers important new perspectives on high-level thought. Explanations sort themselves into several distinct types corresponding to patterns of causation, content domains, and explanatory stances, all of which have cognitive consequences. Although explanations are necessarily incompleteĐ??often dramatically so in laypeopleĐ??those gaps are difficult to discern. Despite such gaps and the failure to recognize them fully, people do have skeletal explanatory senses, often implicit, of the causal structure of the world. They further leverage those skeletal understandings by knowing how to access additional explanatory knowledge in other minds and by being particularly adept at using situational support to build explanations on the fly in real time. Across development and cultures, there are differences in preferred explanatory schemes, but rarely are any kinds of schemes completely unavailable to a group.
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    Annual Review of Psychology 57 (2006), S. 285-315 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Recent studies suggest that cognitive and behavioral interventions have enduring effects that reduce risk for subsequent symptom return following treatment termination. These enduring effects have been most clearly demonstrated with respect to depression and the anxiety disorders. It remains unclear whether these effects are a consequence of the amelioration of the causal processes that generate risk or the introduction of compensatory strategies that offset them and whether these effects reflect the mobilization of cognitive or other mechanisms. No such enduring effects have been observed for the psychoactive medications, which appear to be largely palliative in nature. Other psychosocial interventions remain largely untested, although claims that they produce lasting change have long been made. Whether such enduring effects extend to other disorders remains to be seen, but the capacity to reduce risk following treatment termination is one of the major benefits provided by the cognitive and behavioral interventions with respect to the treatment of depression and the anxiety disorders.
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    Annual Review of Psychology 57 (2006), S. 453-485 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: This chapter reviews research on consumer psychology with emphasis on the topics of categorization, inferences, affect, and persuasion. The chapter reviews theory-based empirical research during the period 1994Đ??2004. Research on categorization includes empirical research on brand categories, goals as organizing frameworks and motivational bases for judgments, and self-based processing. Research on inferences includes numerous types of inferences that are cognitively and/or experienced based. Research on affect includes the effects of mood on processing and cognitive and noncognitive bases for attitudes and intentions. Research on persuasion focuses heavily on the moderating role of elaboration and dual-process models, and includes research on attitude strength responses, advertising responses, and negative versus positive evaluative dimensions.
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    Annual Review of Psychology 57 (2006), S. 55-85 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: It is usually assumed that stressful life events interfere with our ability to acquire new information. However, many studies suggest that stressful experience can enhance processes involved in learning. The types of learning that are enhanced after stressful experiences include classical fear and eyeblink conditioning, as well as processes related to learning about threatening stimuli. Stressful life experiences do seem to interfere with processes involved in memory, often expressed as deficits in the retention or retrieval of information that was acquired prior to and was unrelated to the stressful experience. The trends are limited, as are their implications, because most studies examine adult males, yet the effects of stress on learning processes are influenced by age and sex differences. With respect to mechanisms and anatomical substrates, the effects of stress on learning are usually dependent on the action of stress hormones in combination with neuronal activities within the hippocampus, amygdala, the bed nucleus of the stria terminalis, and the prefrontal cortex.
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    Annual Review of Psychology 57 (2006), S. 199-226 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: What makes a face attractive and why do we have the preferences we do? Emergence of preferences early in development and cross-cultural agreement on attractiveness challenge a long-held view that our preferences reflect arbitrary standards of beauty set by cultures. Averageness, symmetry, and sexual dimorphism are good candidates for biologically based standards of beauty. A critical review and meta-analyses indicate that all three are attractive in both male and female faces and across cultures. Theorists have proposed that face preferences may be adaptations for mate choice because attractive traits signal important aspects of mate quality, such as health. Others have argued that they may simply be by-products of the way brains process information. Although often presented as alternatives, I argue that both kinds of selection pressures may have shaped our perceptions of facial beauty.
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    Annual Review of Psychology 57 (2006), S. 317-344 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Couple therapy research affirms that various approaches to couple treatment produce statistically and clinically significant improvement for a substantial proportion of couples in reducing overall relationship distress. Recent studies have extended these findings in indicating the effectiveness of couple-based interventions for a broad range of coexisting emotional, behavioral, or physical health problems in one or both partners. In contrast to these encouraging results, research also indicates that a sizeable percentage of couples fail to achieve significant gains from couple therapy or show significant deterioration afterward. Research on processes of change and predictors of treatment outcome in couple therapy provides preliminary evidence regarding factors potentially contributing to variable treatment response. The chapter concludes with 12 recommendations regarding future directions in couple therapy research and clinical training.
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    Annual Review of Psychology 57 (2006), S. 401-421 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Personality has consequences. Measures of personality have contemporaneous and predictive relations to a variety of important outcomes. Using the Big Five factors as heuristics for organizing the research literature, numerous consequential relations are identified. Personality dispositions are associated with happiness, physical and psychological health, spirituality, and identity at an individual level; associated with the quality of relationships with peers, family, and romantic others at an interpersonal level; and associated with occupational choice, satisfaction, and performance, as well as community involvement, criminal activity, and political ideology at a social institutional level.
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    Annual Review of Psychology 57 (2006), S. 557-583 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Family violence occurs in many forms; the most prominent are domestic violence, child abuse, and elder abuse. Family violence affects many persons at some point in their life and constitutes the majority of violent acts in our society. Although there has been considerable study of the patterns, risk factors, and interventions for each form of family violence, great controversy still exists within each area. There is growing recognition of an overlap in the patterns, causes, and effective interventions across types of family violence. There is also an increasing awareness of the value of greater integration of theory and research across areas into a family violence approach through an ecological perspective. This review focuses on current knowledge related to these problems and suggests integrative steps to advance knowledge.
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    Annual Review of Pharmacology 46 (2006), S. 235-276 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Nitric oxide (NO) is a small, diffusible, lipophilic free radical gas that mediates significant and diverse signaling functions in nearly every organ system in the body. The endothelial isoform of nitric oxide synthase (eNOS) is a key source of NO found in the cardiovascular system. This review summarizes the pharmacology of NO and the cellular regulation of endothelial NOS (eNOS). The molecular intricacies of the chemistry of NO and the enzymology of NOSs are discussed, followed by a review of the biological activities of NO. This information is then used to develop a more global picture of the pharmacological control of NO synthesis by NOSs in both physiologic conditions and pathophysiologic states.
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    Annual Review of Pharmacology 46 (2006), S. 355-379 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The physiological effects of many extracellular stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid-signaling pathways. These signaling responses include the classically described conversion of PtdIns(4,5)P2 to the Ca2+-mobilizing second messenger Ins(1,4,5)P3 and the protein kinase CĐ??activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. Here we discuss how the family of PLCs elaborates a minimal catalytic core typified by PLC-?? to confer multiple modes of regulation on their phospholipase activities. Although PLC-dependent signaling is prominently regulated by direct interactions with heterotrimeric G proteins or tyrosine kinases, the existence of at least 13 divergent PLC isozymes promises a diverse repertoire of regulatory mechanisms for this class of important signaling pr